Molecular properties of P2X receptors

Abstract

P2X receptors for adenosine tri-phosphate (ATP) are a distinct family of ligand-gated cation channels with two transmembrane domains, intracellular amino and carboxy termini and a large extracellular ligand binding loop. Seven genes (P2X(1-7)) have been cloned and the channels form as either homo or heterotrimeric channels giving rise to a wide range of phenotypes. This review aims to give an account of recent work on the molecular basis of the properties of P2X receptors. In particular, to consider emerging information on the assembly of P2X receptor subunits, channel regulation and desensitisation, targeting, the molecular basis of drug action and the functional contribution of P2X receptors to physiological processes.

Identification and characterization of a novel variant of the human P2X7 receptor resulting in gain of function

“…Aromatic amino acids are associated with recognition of adenine nucleotides in many ATP-binding proteins and are proposed to bind the adenine ring [5,75]. In addition, certain histidine residues within the protein can regulate P2X function [2,5]. It has been reported that glycine residues enhance flexibility in the extracellular loop, raising the possibility that they are involved in conformational changes in P2X receptors upon agonist binding [2,[76][77][78].…”

“…In addition, certain histidine residues within the protein can regulate P2X function [2,5]. It has been reported that glycine residues enhance flexibility in the extracellular loop, raising the possibility that they are involved in conformational changes in P2X receptors upon agonist binding [2,[76][77][78]. Swapping fragments and point mutations in the extracellular loop between rat and mouse P2X 7 receptors also demonstrated that amino acid residues in the ectodomain of the P2X 7 receptor are involved in the differential sensitivity to agonists between species [79].…”

“…Although the role of alternative splicing of the P2X receptor is still unclear, studies have demonstrated that some mis-spliced variants are synthesized as truncated proteins that can interact with full-length receptors to regulate their function [71,90,91]. Unlike the other P2X receptors (P2X [1][2][3][4][5][6] ), P2X 7 is usually considered to form fully functional homotrimers, although evidence for functional P2X 4 /P2X 7 heteromeric receptors has also been reported [97]. Interaction of truncated P2X 7 proteins with full-length P2X 7 through hetero-oligomerization may represent a general paradigm for regulation of protein function by a variant protein encoded by the same gene.…”

“…All of the P2X receptors contain two membrane-spanning domains, intracellular amino and carboxy termini, and an extracellular domain of approximately 280 amino acids containing the ligand-binding site and ten conserved cysteine residues that likely form intrachain disulfide bonds to give secondary structure to the receptor [2][3][4][5]. P2X 7 receptors differ from other P2X receptor subtypes (P2X [1][2][3][4][5][6] ) by an extended cytoplasmic carboxy-terminal tail (240 aa) which may be responsible for the unique ability of P2X 7 to form large pores in the membrane after prolonged agonist stimulation [1]. The P2X 7 receptor exhibits several unusual properties.…”

P2 receptors and platelet function

“…Finally, the P2X 1 receptor is also desensitized, and this occurs very quickly and requires lower concentrations of nucleotides than for the metabotropic receptor P2Y 1 [95,96]. The physiological implications of P2X 1 desensitization are still not well understood but might be related to the need to confine thrombus growth to the site of a lesion and prevent uncontrolled extension of the platelet aggregates.…”